Beyond Hunger: The Structure, Signaling, and Systemic Roles of Ghrelin.

Area of Science:

• Endocrinology and Systems Biology
• Neuroscience
• Pharmacology

Background:

• Ghrelin, the endogenous ligand for growth hormone secretagogue receptor 1a (GHSR1a), has evolved from a simple 'hunger hormone' to a complex regulator of physiology.
• Understanding ghrelin's diverse roles requires synthesizing advances in its biogenesis, signaling pathways, and systemic effects.

Purpose of the Study:

• To provide a comprehensive review of current knowledge on ghrelin biogenesis, signaling, and systems biology.
• To explore the therapeutic potential of targeting the ghrelin system for various physiological and pathological conditions.

Main Methods:

• Literature synthesis of recent advances in ghrelin research, including structural biology, pharmacology, and systems biology.
• Analysis of ghrelin's physiological roles beyond feeding and growth hormone release.
• Review of emerging therapeutic strategies targeting the ghrelin system.

Main Results:

• Ghrelin exhibits complex processing and signaling, with different forms (acyl-ghrelin, des-acyl ghrelin, mini-ghrelins) having distinct activities.
• GHSR1a structure reveals insights into ligand binding, biased signaling, and receptor interactions.
• Ghrelin influences glucose homeostasis, cardiovascular function, immunity, neuroprotection, and stress reactivity, with implications for diseases like Alzheimer's and depression.
• Emerging therapeutic approaches include GOAT inhibitors and strategies modulating LEAP-2.

Conclusions:

• The ghrelin system is a multifaceted and druggable axis with potential for treating inflammatory, neuropsychiatric, addiction, and metabolic disorders.
• Structural and pathway selectivity data are crucial for developing targeted ghrelin-based therapies.
• Ghrelin system modulation offers promise for conditions including obesity, particularly in the post-GLP-1 era.